University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Department of Clinical Pharmacology

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Karonen, Tiina

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2012-11-26T09:43:38Z

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2012-12-04

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dc.date.available

2012-11-26T09:43:38Z

dc.date.issued

2012-12-14

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URN:ISBN:978-952-10-8353-2

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http://hdl.handle.net/10138/37631

dc.description.abstract

Leukotriene receptor antagonists montelukast and zafirlukast are used for asthma and allergic rhinitis. Their marketing authorisations were granted over 15 years ago, before regulatory guidance for drug interaction studies existed. At that time the knowledge of their metabolic pathways was largely based on in vitro studies, in which the main enzymes catalysing the biotransformation of montelukast and zafirlukast were cytochrome P450 (CYP) 2C9 and CYP3A4. Since then the understanding of the importance of CYP enzymes in drug metabolism has increased markedly and also the role of CYP2C8 has been recognised.
Montelukast and zafirlukast are both potent inhibitors of CYP2C8 in vitro, but neither of them has shown inhibitory effect on CYP2C8 in vivo. Montelukast has also been shown to fit well in the active site cavity of CYP2C8 in a crystallography study. These observations led to examine the role of CYP2C8 and CYP3A4 in the metabolism of montelukast in humans, as well as the role of CYP2C8, CYP2C9 and CYP3A4 in the metabolism of zafirlukast in humans.
This work was carried out as four randomised, placebo-controlled cross-over drug interaction studies in healthy volunteers. The CYP2C8 inhibitor gemfibrozil resulted in over fourfold increase of the area under the plasma drug concentration-time curve (AUC) of montelukast, almost blocking the formation of its major metabolite M4. The CYP3A4 inhibitor itraconazole had no effect on the total elimination of montelukast, and decreased only the formation of a minor metabolite M5. The pharmacokinetics of zafirlukast was only affected by CYP2C9 inhibition by fluconazole, which resulted in a 1.6-fold increase of the AUC of zafirlukast. Inhibition of CYP2C8 and CYP3A4 had no effect on the pharmacokinetics of zafirlukast.
The results of this work elucidated the biotransformation pathways of montelukast and zafirlukast in humans. CYP2C8 accounts for about 80% of the metabolism of montelukast, while CYP3A4 has no significant role in it. The main enzyme in the metabolism of zafirlukast in humans is CYP2C9. Concomitant use of CYP2C8 inhibitors with montelukast, or CYP2C9 inhibitors with zafirlukast may increase the risk of concentration dependent adverse drug reactions. With regard to drug interaction studies, a probe drug should be sensitive and relatively safe: according to the present findings montelukast is a promising candidate for a CYP2C8 probe substrate.
These results also highlight the relevance of drug interaction studies and the regulatory guidelines related to them. Especially drugs that have been developed before the existence of these guidelines may be deficiently characterised with regard to their metabolism, leaving the possibility of unrecognized CYP-mediated interactions.